The goal of this proposal is to investigate the regulation commensal-specific T cells that become activated as a result of gastrointestinal (GI) infection. The mammalian GI tract contains over 100 trillion bacteria, many of which share properties with overtly inflammatory pathogens. Immune tolerance to the microbiota is important because dysregulated T cell responses to the commensal microbiota are believed to be an important cause of Inflammatory Bowel Disease (IBD). To prevent chronic inflammation, T cell tolerance to commensal-derived antigens is maintained by a structural and immunological barrier, known as the 'mucosal firewall'. A number of environmental factors, including GI infection, can cause a breach in this barrier that leads to activation of long-lived commensal-specific T cells. However, commensal-specific activation after GI infection does not by necessity lead to chronic gastrointestinal enteropathy or IBD and therefore commensal- specific effector/memory T cells are regulated by unknown mechanisms. In addition to causing a breach in the barrier, GI infection also causes significant changes to the microbiota, allowing for the outgrowth of some commensals, such as E. coli, while inducing the loss of others. The potential impact of this infection-induced transformation of the commensal microbiota and it's associated antigens on the T cell response is not known. GI infection also induces the collapse of GI resident T regulatory cells (Tregs) and those Tregs that remain have been shown to induce the expression of transcription factors and cytokines associated with the anti- pathogen 'Th1' effector state. However, the role of antigen in this process and whether Tregs specific to commensal antigens preferentially survive and initiate the Th1 program is not known. Since GI infection does not necessarily lead to chronic GI enteropathy, there must exist mechanisms for the control of commensal-specific T cells post-activation.
Aim 1 of this proposal will uncover the regulatory mechanisms that control activated commensal-specific T cells and focuses on three non-exclusive possibilities: 1) reformation of the barrier preventing chronic activation 2) control by Tregs and 3) control by the cytokine interleukin 10.
Aim 1 will also address potential consequences of the shift in the microbiota following infection via the creation of novel tools to follow the T cell response to commensal E. coli after GI infection.
Aim 2 will address whether commensal-specific Tregs preferentially survive and differentiate to a Th1 state after infection and also whether such 'converted' Tregs survive long-term as a potentially dangerous population of commensal-specific effector T cells. Completion of these aims, along with associated training opportunities associated with this proposal will establish the necessary foundation for my career as an independent investigator.
Inflammatory Bowel Disease (IBD) is a debilitating disease that affects over 1.4 million Americans and costs over 6 billion dollars to treat yearly, but unfortunately the causes of IBD remain largely unknown. This proposal seeks to examine whether the activation of commensal-specific T cells by gastrointestinal infection, in concert with immune dysregulation, leads to the development of disease. Understanding the etiology of IBD will contribute greatly to our ability to treat patients and this work may lead to therapies targetd to critical immune- commensal interactions that contribute to the disease.
| Chiaranunt, Pailin; Tometich, Justin T; Ji, Junyi et al. (2018) T Cell Proliferation and Colitis Are Initiated by Defined Intestinal Microbes. J Immunol 201:243-250 |
| Hand, Timothy W; Vujkovic-Cvijin, Ivan; Ridaura, Vanessa K et al. (2016) Linking the Microbiota, Chronic Disease, and the Immune System. Trends Endocrinol Metab 27:831-843 |
| Hand, Timothy W (2016) The Role of the Microbiota in Shaping Infectious Immunity. Trends Immunol 37:647-658 |
